PURPOSE:Concurrent chemoradiation therapy is the standard therapy for limited-stage small cell lung cancer (LS-SCLC) but induces cancer therapy-induced thrombocytopenia (CTIT), which leads to treatment delays. This study aims to assess the efficacy and safety of prophylactic recombinant human thrombopoietin (rhTPO) in preventing CTIT in this patient population. METHODS AND MATERIALS:This prospective, multicenter, phase II trial was conducted across 14 Chinese centers. LS-SCLC patients receiving etoposide plus cisplatin or carboplatin chemotherapy with concurrent radiation therapy were given subcutaneous rhTPO (300 IU/kg/d) on days 1-5, 8-12, and 15-19 during radiation therapy. rhTPO treatment was stopped if platelet count reached ≥300 × 109/L or increased by ≥100 × 109/L from baseline. Primary endpoints were the nadir and peak platelet count. RESULTS:From March 8, 2024, to October 10, 2024, 56 LS-SCLC patients were enrolled. During the rhTPO treatment period, nadir platelet count (×109/L) was 128.54 ± 54.15, and peak platelet count reached 409.23 ± 173.50. Overall incidence of CTIT was 33.9% (19/56), including 8.9% (5/56) grade 3, and no grade 4-5 events. A total of 78.9% of patients (15/19) experienced platelet count recovery to ≥100 × 109/L during the rhTPO treatment period. Median time for platelet count recovery from <100 × 109/L to ≥100 × 109/L was 8 days (95% CI, 6-14). Multivariable logistic regression analysis revealed that low baseline platelet count (<150 × 109/L) was an independent risk factor for developing CTIT (odds ratio, 4.26; 95% CI, 1.08-16.78; P = .038). No patients required platelet transfusions or experienced radiation therapy interruptions, and only one patient required a reduction in the dose of chemotherapy throughout the entire study. Moreover, no serious adverse events were reported. rhTPO-related adverse reactions were infrequent and predominantly grade 1 (eg, transient platelet elevation). CONCLUSIONS:Prophylactic rhTPO during concurrent chemoradiation therapy for patients with LS-SCLC demonstrated a potential benefit in maintaining platelet counts with a low incidence of CTIT. These findings support further investigation of rhTPO as a preventive strategy for high risk CTIT patients.

Background: Early-stage high-grade lung invasive adenocarcinoma (IAC) has poor prognosis and is hard to identify using conventional radiological assessment. Current reliance on postoperative histology to identify high-grade subtypes delays risk-adapted surgical planning. Three-dimensional (3D) vision transformers (ViTs) may improve prediction by modeling long-range dependencies in computed tomography (CT) scans. We aimed to develop and validate 3D-ViT and Swin Transformer (SwinT) for preoperative CT-based prediction of early-stage high-grade IAC subtypes (micropapillary/solid), benchmarking against ResNet. Methods: A multicenter cohort of 1028 patients with surgically confirmed early-stage lung adenocarcinoma was divided into training (n = 806), validation (n = 100), and external test (n = 122) sets. 3D-ViT, SwinT, and ResNet models were trained on CT to classify nodules harboring high-grade histologic patterns. A novel decision-aid tool for IAC surgery was provided. Performance was evaluated using area under the curve (AUC), accuracy, sensitivity, specificity, and precision. Attention mapping was performed to interpret 3D-ViT decision-making. Results: The 3D-ViT model achieved AUC values of 0.856 (95% CI: 0.845–0.877) (validation) and 0.806 (95% CI: 0.790–0.816) (testing), compared to 0.854 (95% CI: 0.841–0.872) (validation) and 0.760 (95% CI: 0.743–0.776) (testing) for the ResNet baseline. 3D-ViT showed balanced accuracy, sensitivity, specificity, and precision in the validation set. In external testing, 3D-ViT significantly outperformed ResNet in all metrics with P < 0.01. The SwinT-based AlignSen model from decision-aid tool prioritized sensitivity for high-grade IAC (88.0% validation, 93.4% testing), while maintaining specificity (76.0% validation, 54.1% testing) which significantly outperformed ViT and ResNet-based AlignSen models’ specificity (60.0% and 54% validation, 52.5% and 24.6% testing, respectively). Attention maps highlighted 3D nodule heterogeneity and peripheral irregularities. Conclusion: The 3D-ViT model demonstrated robust accuracy and generalizability in predicting high-grade IAC subtypes using CT images. Integration of preoperative SwinT into clinical workflows may offer a viable alternative to intraoperative pathology subtyping, potentially reducing reliance on frozen sections while optimizing surgical planning.

This secondary analysis of a randomized clinical trial reports the long-term survival rates and cancer- and noncancer-related causes of death associated with concurrent chemoradiotherapy with S-1 in older patients in China. QuestionIs concurrent chemoradiotherapy (CCRT) with S-1 associated with differences in survival compared with radiotherapy alone in older patients with esophageal cancer (EC)?FindingsIn this secondary analysis of a randomized clinical trial involving 298 patients with EC, the first prospective long-term data (median follow-up of 87 months) on treatment outcomes were reported. Patients in the CCRT with S-1 group showed significantly better overall survival than those in the RT-alone group, and long-term follow-up revealed no increase in noncancer-related mortality among patients receiving CCRT with S-1.MeaningThese results support CCRT with S-1 as an effective and tolerable treatment option for older patients with EC, addressing the critical evidence gap for this underrepresented population. ImportanceMost older patients with esophageal cancer (EC) are unable to complete standard platinum-based concurrent chemoradiotherapy (CCRT) due to reduced organ reserve, comorbidities, and malnutrition. A new treatment option-CCRT with S-1-has been found to have high efficacy and fewer toxic effects for this population, yet long-term data supporting its use remain limited.ObjectiveTo evaluate the long-term outcomes of CCRT with S-1 vs radiotherapy (RT) alone in older patients with EC.Design, Setting, and ParticipantsThis secondary analysis of a phase 3 randomized clinical trial conducted at 23 centers in China was not prespecified in the trial protocol. Patients aged 70 to 85 years with histologically confirmed EC were enrolled between June 1, 2016, and August 31, 2018. Data cutoff date was February 1, 2025, with an additional follow-up of 54 months beyond the primary analysis. Data were analyzed from February 1 to April 1, 2025.InterventionsPatients were randomly assigned 1:1 to receive CCRT with S-1 consisting of 54 Gy in 30 fractions with S-1, 70 mg/m2 per day on days 1 to 14 and 29 to 42, or RT alone consisting of 60 Gy in 30 fractions, 2.0 Gy per day 5 days per week.Main Outcomes and MeasuresThe primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS), cause-specific mortality, cumulative incidence of death from EC or other reasons, and cumulative incidences of locoregional or distant metastasis during treatment or relapse after treatment.ResultsA total of 298 patients (median [IQR] age, 77 [74-79] years; 180 males [60.4%]) were enrolled. There were 151 patients (50.7%) clinically diagnosed with stage III to IV disease. With a median (IQR) follow-up of 87 (85-92) months, the median OS was 24.7 (95% CI, 21.2-37.6) months in the CCRT group and 15.1 (95% CI, 12.4-18.6) months in the RT group (hazard ratio [HR], 0.69; 95% CI, 0.53-0.90; P = .005). The 5-year OS rates were 33.5% (95% CI, 26.7%-42.1%) and 24.4% (95% CI, 18.3%-32.4%) for the CCRT and RT groups, respectively; the 8-year OS rates were 26.2% and 16.1%, respectively. The median PFS was 18.7 (95% CI, 13.1-25.8) months in the CCRT group and 9.2 (95% CI, 7.9-12.7) months in the RT group (HR, 0.69; 95% CI, 0.54-0.90; P = .005). Cause-specific analyses showed reduced EC-related mortality with CCRT (HR, 0.67; 95% CI, 0.50-0.89; P = .005), with 8-year absolute risks of 58.5% vs 72.9%, respectively, and no excess noncancer-related mortality.Conclusions and RelevanceIn this secondary analysis of a randomized clinical trial, long-term results showed that CCRT with S-1 was associated with a sustained survival benefit compared with RT alone, without increased noncancer-related mortality. This finding supports CCRT with S-1 as the preferred regimen for patients aged 70 to 85 years with EC.Trial RegistrationClinicalTrials.gov Identifier: NCT02813967

Importance:Most older patients with esophageal cancer (EC) are unable to complete standard platinum-based concurrent chemoradiotherapy (CCRT) due to reduced organ reserve, comorbidities, and malnutrition. A new treatment option-CCRT with S-1-has been found to have high efficacy and fewer toxic effects for this population, yet long-term data supporting its use remain limited. Objective:To evaluate the long-term outcomes of CCRT with S-1 vs radiotherapy (RT) alone in older patients with EC. Design, Setting, and Participants:This secondary analysis of a phase 3 randomized clinical trial conducted at 23 centers in China was not prespecified in the trial protocol. Patients aged 70 to 85 years with histologically confirmed EC were enrolled between June 1, 2016, and August 31, 2018. Data cutoff date was February 1, 2025, with an additional follow-up of 54 months beyond the primary analysis. Data were analyzed from February 1 to April 1, 2025. Interventions:Patients were randomly assigned 1:1 to receive CCRT with S-1 consisting of 54 Gy in 30 fractions with S-1, 70 mg/m2 per day on days 1 to 14 and 29 to 42, or RT alone consisting of 60 Gy in 30 fractions, 2.0 Gy per day 5 days per week. Main Outcomes and Measures:The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS), cause-specific mortality, cumulative incidence of death from EC or other reasons, and cumulative incidences of locoregional or distant metastasis during treatment or relapse after treatment. Results:A total of 298 patients (median [IQR] age, 77 [74-79] years; 180 males [60.4%]) were enrolled. There were 151 patients (50.7%) clinically diagnosed with stage III to IV disease. With a median (IQR) follow-up of 87 (85-92) months, the median OS was 24.7 (95% CI, 21.2-37.6) months in the CCRT group and 15.1 (95% CI, 12.4-18.6) months in the RT group (hazard ratio [HR], 0.69; 95% CI, 0.53-0.90; P = .005). The 5-year OS rates were 33.5% (95% CI, 26.7%-42.1%) and 24.4% (95% CI, 18.3%-32.4%) for the CCRT and RT groups, respectively; the 8-year OS rates were 26.2% and 16.1%, respectively. The median PFS was 18.7 (95% CI, 13.1-25.8) months in the CCRT group and 9.2 (95% CI, 7.9-12.7) months in the RT group (HR, 0.69; 95% CI, 0.54-0.90; P = .005). Cause-specific analyses showed reduced EC-related mortality with CCRT (HR, 0.67; 95% CI, 0.50-0.89; P = .005), with 8-year absolute risks of 58.5% vs 72.9%, respectively, and no excess noncancer-related mortality. Conclusions and Relevance:In this secondary analysis of a randomized clinical trial, long-term results showed that CCRT with S-1 was associated with a sustained survival benefit compared with RT alone, without increased noncancer-related mortality. This finding supports CCRT with S-1 as the preferred regimen for patients aged 70 to 85 years with EC. Trial Registration:ClinicalTrials.gov Identifier: NCT02813967.

e20562 Background: For patients with advanced NSCLC who fail first-line chemotherapy combined with immunotherapy, docetaxel as standard second line treatment often yields disappointing results. Immune rechallenge with alternative immune checkpoint inhibitors(ICIs) may enhance efficacy. Trilaciclib, a CDK4/6 inhibitor, protects hematopoietic stem cells during chemotherapy and potentially exhibits immune-enhancing properties when combined with ICIs. Further research is needed to explore trilaciclib's potential in improving the outcomes of second-line treatment combinations in advanced NSCLC. Methods: This prospective, multicenter, open-label, randomized, phase II trial was conducted at five centers in China in patients with advanced NSCLC who had failed the first-line treatment with platinum-based chemotherapy combined with PD-1 inhibitors. Patients were randomly assigned (1:1:1) to receive trilaciclib (240 mg/m 2 ) before docetaxel (intravenous infusion of 75 mg/m 2 ), and envafolimab (300 mg, subcutaneous injection) every 3 weeks in cohort A, docetaxel and envafolimab in cohort B, docetaxel alone in cohort C until disease progression, unacceptable toxicity, or death (whichever occurred first). The primary endpoint was PFS. Results: As of December 12, 2024, a total of 25 pts were enrolled, with 10 in cohort A, 8 in cohort B, and 7 in cohort C. Among the 25 pts, 17 pts underwent at least one efficacy evaluation. In cohort A, 7/10(70%) pts achieved stable disease(SD); in cohort B, 1/8(12.5%) achieved partial response (PR) and 2/8(25%) achieved SD; and in cohort C, 2/7(28.6%) achieved SD. Hematological toxicity occurred in 17/25 (68%) pts during the first cycle, with a lower incidence in cohort A compared to cohorts B and C. Conclusions: Trilacilib prior to envafolimab and docetaxel yielded potential clinical efficacy, and trilacilib may help alleviate the hematological toxicity of combination therapy in the second-line treatment of advanced NSCLC. PFS data, OS data and and myeloprotection with trilaciclib will be updated in the future. Clinical trial information: NCT05910034 . Antitumor efficacy and hematological adverse events during the first treatment cycle. CohortA(n=10) CohortB(n=8) CohortC(n=7) Antitumor Efficacy, n(%) BOR PR 0 1 (12.5) 0 SD 7 (70.0) 2 (25.0) 2 (28.6) PD 1 (10.0) 1 (12.5) 3 (42.9) NE 2 (20.0) 4 (50.0) 2 (28.6) ORR 0 1 (12.5) 0 DCR 7 (70.0) 3 (37.5) 2 (28.6) Hematological Adverse Events, n(%) Neutropenia 5 (50.0) 5 (62.5) 6 (85.7) ≥ Grade 3 Neutropenia, n(%) 4 (40.0) 4 (50) 5 (71.4) Anemia, n(%) 1 (10.0) 1 (12.5) 3 (42.8) ≥ Grade 3 Anemia, n(%) 0 0 0 Thrombocytopenia, n(%) 1 (10.0) 1 (12.5) 0 ≥ Grade 3 Thrombocytopenia, n(%) 0 0 0 Double hematological events, n(%) 2 (20.0) 2 (25.0) 4 (57.1)

Central nervous system (CNS) metastases remain a significant challenge in the management of EGFR-variant non–small cell lung cancer (NSCLC). To evaluate the activity and safety of high-dose aumolertinib in patients with untreated EGFR-variant NSCLC and brain metastases. This was a phase 2 nonrandomized clinical trial conducted at 10 centers in China. Patients with untreated EGFR-variant metastatic NSCLC and brain metastases were enrolled between July 6, 2021, and August 31, 2022. The data cutoff date was October 10, 2024. Patients received aumolertinib, 165 mg, orally once daily until disease progression or unacceptable toxic effects. The primary end point was 12-month progression-free survival (PFS) rate assessed by investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1. A total of 63 patients (39 female [61.9%]; median age, 60 [range, 47-76] years) were enrolled (full analysis set), and 49 had at least 1 measurable brain lesion (CNS evaluable-for-response set). Median follow-up duration was 28.8 months (95% CI, 27.0-29.8). In the full analysis set, the 12-month PFS rate was 62.1% (95% CI, 48.7-73.0), the median PFS was 20.5 months (95% CI, 12.0-26.9), the 12-month intracranial PFS rate was 76.8% (95% CI, 63.2-85.9), and the median intracranial PFS and overall survival were not reached. Systemic and intracranial objective response rates per RECIST 1.1 were 56 of 63 (88.9% [95% CI, 78.4-95.4]) and 52 of 63 (82.5% [95% CI, 70.9-90.9]) in the full analysis set and 43 of 49 (87.8% [95% CI, 75.2-95.4]) and 42 of 49 (85.7% [95% CI, 72.8-94.1]) in the CNS evaluable-for-response set, respectively. The most common grade 3 or 4 treatment-related adverse event was increased blood creatine phosphokinase (17 participants [27.0%]). No treatment-related deaths occurred. EGFR variant clearance in plasma circulating tumor DNA at day 1 of cycle 2 was independently associated with longer PFS (hazard ratio, 0.14 [95% CI, 0.04-0.47]; P = .001). The findings of this nonrandomized clinical trial suggest that high-dose aumolertinib is associated with long-term survival benefit in patients with untreated EGFR-variant NSCLC and brain metastases, with a manageable safety profile. ClinicalTrials.gov Identifier: NCT04808752

Background Brain metastases are a common complication in patients with non-small-cell lung cancer (NSCLC) lacking actionable driver mutations, with limited treatment options and poor prognosis. We aimed to investigate the efficacy and safety of brain radiotherapy combined with camrelizumab and platinum-doublet chemotherapy in patients with newly diagnosed advanced NSCLC and brain metastases. Methods This multicentre, single-arm, phase 2 trial was done across nine tertiary hospitals in China. Eligible patients were aged 18 years or older, had newly diagnosed brain metastases from NSCLC with no actionable driver mutations (EGFR, ALK, or ROS1), and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients were treated with stereotactic radiosurgery or whole-brain radiotherapy combined with camrelizumab (200 mg intravenously once every 3 weeks) and investigator-selected platinum-doublet chemotherapy (pemetrexed 500 mg/m(2) plus platinum [carboplatin, area under curve (AUC) of 5, or cis-platinum 75 mg/m(2)] for non-squamous NSCLC, and nab-paclitaxel 260 mg/m(2) plus platinum [carboplatin AUC 5, or cis-platinum 75 mg/m(2)] for squamous NSCLC) for four to six cycles. Patients with controlled disease then received maintenance treatment with camrelizumab alone (200 mg intravenously once every 3 weeks; for squamous NSCLC) or camrelizumab plus pemetrexed (500 mg/m(2) every 3 weeks; for non-squamous NSCLC). The primary endpoint was 6-month progression-free survival rate in the full analysis set, which included all patients who received at least one dose of study treatment regardless of whether they had measurable brain lesions per RECIST 1.1. The trial was registered with ClinicalTrials.gov, NCT04291092, and is ongoing. Findings Between May 6, 2020, and Jan 30, 2023, 67 patients were assessed for eligibility. Two patients were excluded (brain lesions less than 5 mm) and 65 patients were enrolled and treated. Median age was 66 years (IQR 62-70). 60 (92%) of 65 patients were male and five (8%) were female. All 65 patients were Han Chinese. 50 (77%) of 65 patients had non-squamous NSCLC and 46 (71%) were symptomatic. The 6-month progression-free survival rate was 717% (95% CI 589-811) during the median follow-up of 141 months (IQR 90-203; data cutoff Dec 13, 2023). The most common grade 3-4 treatment-related adverse events were decreased neutrophil count (14 [22%] of 65 patients), decreased white blood cell count (ten [15%]), decreased platelet count (ten [15%]), and decreased lymphocyte count (nine [14%]). Neurological toxic effects of grade 3 occurred in three (5%) of 65 patients. Radiation necrosis occurred in three (5%) of 65 patients; all were grade 1 or 2. There were no treatment-related deaths. Interpretation Brain radiotherapy combined with camrelizumab and platinum-doublet chemotherapy shows promising efficacy and manageable toxicity and could be a potential treatment option for patients with brain metastases from NSCLC. Randomised controlled trials will be required to confirm these findings.

BACKGROUND:The combination of anlotinib with chemotherapy has demonstrated encouraging efficacy in the treatment of nonsmall cell lung cancer (NSCLC). The objective of this phase 1/2 trial was to establish the maximum tolerated dose of anlotinib in combination with docetaxel and to assess the efficacy and safety of this regimen in patients with advanced NSCLC who had progressed after platinum-based chemotherapy. METHODS:In the phase 1 trial, eight patients were enrolled to determine the maximum tolerated dose, which was identified as 10 mg for anlotinib in combination with docetaxel. In the phase 2 trial, in total, 88 patients were randomized, with 57 receiving anlotinib at the established maximum tolerated dose alongside docetaxel and 31 receiving docetaxel monotherapy. Tumor response was evaluated in 88 patients. RESULTS:In the phase 2 study, the combination of anlotinib and docetaxel demonstrated a significant improvement in progression-free survival compared with docetaxel monotherapy (median, 5.39 vs. 2.56 months; hazard ratio, 0.36; 95% confidence interval, 0.21-0.63; p = .0002). The objective response rate was also superior in the combination group (26.32% vs. 6.45%). The median overall survival was 16.82 months for the combination group versus 9.86 months for the monotherapy group (hazard ratio, 0.89; 95% confidence interval, 0.47-1.66; p = .7114). Safety analysis included 96 patients, and the most frequent treatment-emergent adverse events were decreased neutrophil count and decreased white blood cell count. CONCLUSIONS:The addition of anlotinib to docetaxel was characterized by a manageable safety profile and also resulted in a significant improvement in progression-free survival among patients with advanced NSCLC who had previously failed platinum-based chemotherapy (ClinicalTrials.gov identifier NCT03726736).

Importance:Central nervous system (CNS) metastases remain a significant challenge in the management of EGFR-variant non-small cell lung cancer (NSCLC). Objective:To evaluate the activity and safety of high-dose aumolertinib in patients with untreated EGFR-variant NSCLC and brain metastases. Design, Setting, and Participants:This was a phase 2 nonrandomized clinical trial conducted at 10 centers in China. Patients with untreated EGFR-variant metastatic NSCLC and brain metastases were enrolled between July 6, 2021, and August 31, 2022. The data cutoff date was October 10, 2024. Interventions:Patients received aumolertinib, 165 mg, orally once daily until disease progression or unacceptable toxic effects. Main Outcomes and Measures:The primary end point was 12-month progression-free survival (PFS) rate assessed by investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1. Results:A total of 63 patients (39 female [61.9%]; median age, 60 [range, 47-76] years) were enrolled (full analysis set), and 49 had at least 1 measurable brain lesion (CNS evaluable-for-response set). Median follow-up duration was 28.8 months (95% CI, 27.0-29.8). In the full analysis set, the 12-month PFS rate was 62.1% (95% CI, 48.7-73.0), the median PFS was 20.5 months (95% CI, 12.0-26.9), the 12-month intracranial PFS rate was 76.8% (95% CI, 63.2-85.9), and the median intracranial PFS and overall survival were not reached. Systemic and intracranial objective response rates per RECIST 1.1 were 56 of 63 (88.9% [95% CI, 78.4-95.4]) and 52 of 63 (82.5% [95% CI, 70.9-90.9]) in the full analysis set and 43 of 49 (87.8% [95% CI, 75.2-95.4]) and 42 of 49 (85.7% [95% CI, 72.8-94.1]) in the CNS evaluable-for-response set, respectively. The most common grade 3 or 4 treatment-related adverse event was increased blood creatine phosphokinase (17 participants [27.0%]). No treatment-related deaths occurred. EGFR variant clearance in plasma circulating tumor DNA at day 1 of cycle 2 was independently associated with longer PFS (hazard ratio, 0.14 [95% CI, 0.04-0.47]; P = .001). Conclusions and Relevance:The findings of this nonrandomized clinical trial suggest that high-dose aumolertinib is associated with long-term survival benefit in patients with untreated EGFR-variant NSCLC and brain metastases, with a manageable safety profile. Trial Registration:ClinicalTrials.gov Identifier: NCT04808752.

2007 Background: Central nervous system (CNS) metastases is inevitable for epidermal growth factor receptor (EGFR)mutant non-small cell lung cancer (NSCLC). The pre-specified analysis of the FLAURA and other phase III studies has unveiled encouraging results in patients with CNS metastasis. Nevertheless, the availability of limited biomarkers poses a challenge for the early prediction of clinical effects. Methods: We launched a prospective, open-label, single-arm clinical trial across multiple centers (ACHIEVE). Participants, all diagnosed with EGFR-mutated NSCLC with CNS metastases, received first line treatment with high dose Almonertinib through once-daily oral administration, with each dose being 165 mg. The primary endpoints focused on progression free survival (PFS). Concurrently, we gathered baseline and end-of-first-cycle plasma samples, subjecting them to a comprehensive 520 gene-based sequencing analysis. Results: A total of 63 patients were selected and enrolled between Jul 6,2021 and Aug 31,2022. The median follow-up time, until Nov 30,2023, was 538 days. The confirmed Overall Response Rate (ORR) was 88.9% (56/63), while 42.9% (27/63) of patients progressed, with a median PFS of 17.71 months (11.96-NE). Moreover, a notable 88.9% (56/63) of intracranial lesions achieved either a Complete Response (CR) in 21 cases (33.3%) or a Partial Response (PR) in 35 cases (55.6%). To guide and enhance clinical strategy selection, we conducted a comprehensive biomarker evaluation using cell-free DNA (cfDNA) sequencing. Of the 60 baseline plasmas that passed quality control, 81.7% (46/60) were identified as having at least one somatic mutation (ctDNA+). No significant differences were observed between ctDNA+ and ctDNA- groups in terms of ORR (p = 0.33), intracranial ORR (p = 0.499), PFS (p = 0.363, HR = 1.75), and intracranial PFS (p = 0.562, HR = 1.56). Furthermore, we developed a novel algorithm named MedSR (Median Short cfDNA fragment Ratio) based on cfDNA fragment distribution patterns to quantify ctDNA amount. Notably, higher baseline MedSR values (above the median) predicted significantly poorer PFS (p = 0.001, HR = 0.22) and intracranial PFS (p = 0.067, HR = 0.35), demonstrating superior efficacy compared to traditional cfDNA biomarkers like maxAF. On Cycle 2, those achieving ctDNA clearance in C2D1, regardless of their ctDNA status on baseline, exhibited significantly improved PFS (p < 0.001, HR = 4.63) and intracranial PFS (p = 0.001, HR = 5.71). Conclusions: High dose Almonertinib exhibited promising efficacy and maintained tolerable safety as a first-line therapy in EGFR-mutated NSCLC with CNS metastases. The novel MedSR score demonstrated potential value in predicting the efficacy of TKI treatment. Clinical trial information: NCT04808752 .

This multicohort phase II trial (ALTER-G-001; NCT05262335) aimed to assess the efficacy of first-line anlotinib plus chemotherapy for gastrointestinal (GI) cancer patients with unresectable liver metastases. Eligible patients with colorectal cancer (Cohort A) or noncolorectal and nonesophageal GI cancer (Cohort C) received six cycles of anlotinib plus standard chemotherapeutic regimens followed by anlotinib plus metronomic capecitabine as a maintenance therapy. Liver metastasectomy can be performed when liver metastases are converted to resectable lesions. The primary outcome was the investigator-confirmed objective response rate (ORR) in the intention-to-treat population. Among the 47 patients in Cohort A, the ORR was 40.4% (95% CI 26.4-55.7), including 1 with a complete response (CR) and 18 who achieved a partial response (PR). The median progression-free survival (PFS) was 8.7 months (95% CI 7.3-NE), and the median overall survival (OS) was not reached. In Cohort C, 14 of 44 patients achieved a PR, with an ORR of 31.8% (95% CI 18.6-47.6). The PFS and OS were 5.8 months (95% CI 4.8-6.5) and 11.4 months (95% CI 5.8-19.3), respectively. The liver metastasectomy rate in patients with liver-limited disease was 22.7% (5/22) in Cohort A and 6.7% (2/30) in Cohort C. For pancreatic cancer patients, the ORR of the efficacy-evaluable population was 36.0% (9/25), and those with liver-limited metastasis had better survival. Moreover, no new safety concerns emerged. In conclusion, an anlotinib-based first-line regimen demonstrated promising antitumor activity among GI cancer patients with unresectable liver metastases and led to liver metastasectomy in selected patients.

Rationale:Blockade of programmed death protein 1 (PD-1), have been observed to have quite good efficacy in recurrent and metastatic cervical cancer. Generally, we believe that the biomarkers of PD-1 inhibitors are programmed cell death-ligand 1, tumor mutational burden, high microsatellite instability, or deficient mismatch repair. However, in the case reported below, we observed that the patient with negative existing predictive biomarkers have significant benefits after zimberelimab monotherapy, indicating that there were other biomarkers that may predict immunotherapy efficacy. However, currently, no one has explored and studied the other potential biomarkers of PD-1 inhibitors.Patient concerns:A 51-year-old patient, diagnosed with cervical adenocarcinoma nearly 11 years ago, requested treatment.Diagnoses:The next-generation sequencing has shown PIK3CA E545K, SMAD4 1309-1G, and ALK E717K gene mutations, receptor tyrosine kinase 2 (ErbB-2) amplification, microsatellite stability, and low tumor mutational burden of 6.3 mutations per megabase. And immunohistochemistry revealed that the tumor was programmed cell death-ligand 1 negative.Intervention:Zimberelimab monotherapy was accepted as third-line treatment.Outcomes:The patient had received zimberelimab for nearly 10 months, the best tumor response was PR (Response Evaluation Criteria in Solid Tumours) and no noticeable adverse reactions were observed.Lessons:PIK3CA-E542K, ErbB2 amplification, and SMAD4 mutations could be potential biomarkers for PD-1 inhibitors, but a single instance is insufficient to validate the hypotheses. A larger number of patients or more clinical data will be necessary to determine whether these gene mutations are appropriate biomarkers for patients when treatment with PD-1 inhibitors.

e16268 Background: Patients (pts) with advanced gastrointestinal (GI) tumors, such as colorectal cancer (CRC), esophageal squamous cell carcinoma (ESCC), gastric cancer (GC) or pancreatic cancer (PC), often developed liver metastases (LMs) with poor prognosis. Currently, there was no formal option for those, thus, more effective regimens were needed. Previously clinical trials had demonstrated anlotinib plus chemotherapy as first-line regimen had encouraging efficacy and safety in advanced CRC and ESCC, especially in pts with LMs. Therefore, we conducted a phase II trial evaluate efficacy and safety of anlotinib plus chemotherapy as first-line treatment in pts with unresectable LMs GI tumors. Methods: A total of 116 eligible pts with unresectable LMs gastrointestinal tumors and without previous systemic treatment would be divided into cohort A (mCRC), cohort B (ESCC) and cohort C (others, such as PC, GC, etc.,). All enrolled patients received 6 cycles (3 weeks per cycle) of induction therapy, cohort A receiving anlotinib (12mg, po, qd, d1-d14), oxaliplatin (130 mg/m 2 , iv, d1) and capecitabine (850 mg/m 2 , po, bid, d1-d14), cohort B receiving anlotinib, cisplatin (60-750 mg/m 2 , i.v., d1/d1-3) and paclitaxel (135 mg/m 2 , i.v., d1) or docetaxel (75 mg/m 2 , i.v., d1) and cohort C receiving anlotinib plus standard chemotherapy. Then, pts in all cohorts without PD and radical resection received anlotinib and metronomic capecitabine (500mg, po. bid, d1-21, q3w) until PD or unacceptable toxicity. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints included DoR, PFS, OS, DCR, radical resection rate for LMs and safety. Results: As of February 8 th , 2023, 55 pts were enrolled, 23 in cohort A, 2 in cohort B and 30 in cohort C (including 18 PC, 6 GC, 5 biliary tract cancer (BTC) and others), with a median age of 62.5 years old (range 34-74), 67.3% of male, 89.1% of ECOG PS 1. 70.9% of pts had LMs only. After induction therapy, 7 pts (5 CRC, 1 PC, 1 BTC) received surgical resection. In 24 evaluable pts in cohort C, 12 had partial response (PR), 9 had stable disease (SD). ORR was 50.0% and DCR was 87.5%. Among 13 evaluable pts with PC, 7 had PR, 5 had SD, with an ORR of 53.8%. In 15 evaluable pts in cohort A, 11 reached PR and 4 had SD. The ORR of cohort A was 73.3% and DCR was 100.0%. For one evaluable ESCC pts in cohort B, the best response was PR. The median PFS was not reached. 50.9% of pts had treatment emergent adverse events (TEAEs). Incidence of grade 3/4 TEAEs was 16.4%, mainly included white blood cell decreased (7.3%), neutropenia and hypertension (5.5%). Conclusions: Anlotinib plus chemotherapy showed significant efficacy and manageable toxicities as first-line treatment in advanced gastrointestinal tumors with LMs, especially in pancreatic cancer, which might provide a new treatment strategy for those. Clinical trial information: NCT05262335 .

Background:Malnutrition is particularly common in patients undergoing radiotherapy for head and neck cancers (HNC) and esophageal cancers (EC). Proper nutritional management plays an important role in improving the nutritional status and reducing complications in patients undergoing radiotherapy for malignancy. With most nutrition studies limited to the nutritional management of patients during hospitalization or after discharge, there is a lack of research evidence on the nutritional management of patients in combination with out-of-hospital. The aim of this study was to evaluate the effect of the hospital-community-family (HCF) nutritional management model on nutritional status and radiotherapy complications in EC and HNC radiotherapy patients.Methods:Between October 2019 and October 2021, a total of 116 EC and HNC radiotherapy patients were randomized into control group (conventional nutritional support) and experimental group (HCF-model nutritional management), and assessed weekly for 3 months. The primary endpoint was the patient's Nutrition Risk Screening 2002 (NRS2002) score, Scored Patient-Generated Subjective Global Assessment (PG-SGA), weight change, and Eastern Cooperative Oncology Group (ECOG) score from baseline level to 3 months after the end of treatment. The secondary endpoints were the incidence of albumin, hemoglobin, hematological parameters, and radiotherapy complications.Results:A total of 95 patients (47 in the control group and 48 in the experimental group) completed the study. At 3 months after treatment, NRS2002 (P=0.028) and PG-SGA (P=0.022) decreased, and albumin was higher (P=0.001) than at the beginning of treatment in HCF group. Weight decreased (P<0.001) and PG-SGA was higher after 3 months of treatment (P=0.012) in the control group. PG-SGA (P<0.001), NRS2002 (P<0.001), and ECOG (P=0.006) in the HCF group at the end of the 3-month treatment period were lower in the conventional group (P<0.05). The incidence of radiation mucositis (P=0.018)and radiation dermatitis (P=0.028) in the HCF nutrition management group was significantly reduced (P<0.05).Conclusions:HCF-model nutritional management significantly improved the nutritional status and reduced the incidence and severity of radiation mucositis and dermatitis for EC and HNC radiotherapy patients. These findings suggest that HCF-model nutritional management is a promising nutritional management model.Trial Registration:Chinese Clinical Trial Registry identifier: ChiCTR2300068399.

AbstractBackgroundPatients with non‐small‐cell lung cancer (NSCLC) and uncommon EGFR alterations typically have worse treatment outcomes than patients with classically EGFR‐mutated NSCLC. This study aimed to investigate the efficacy and safety of PD‐1 blockade with sintilimab plus anti‐angiogenic treatment with anlotinib in patients with NSCLC harboring uncommon EGFR mutations.MethodsPatients with metastatic NSCLC harboring uncommon EGFR mutations after two previous treatments, including a platinum‐based chemotherapy regimen and a targeted treatment (or chemotherapy only for patients harboring EGFR ex20ins), received sintilimab combined with anlotinib. The primary endpoint was objective response rate (ORR).ResultsAt data cutoff (September 27, 2022), median follow‐up was 22.3 months (range, 1.2–37.6). Among 21 enrolled patients, 12 had EGFR ex20ins and nine had other uncommon EGFR mutations such as L861Q, G719A, and G709X. Overall, eight patients (38.1%) achieved an objective response, and 18 (85.7%) achieved disease control. Median (95% CI) progression‐free survival (PFS) was 7.0 (5.4–8.6) months, and median overall survival (OS) was 20.0 (15.6–24.4) months. The 12‐month PFS rate (95% CI) was 22.2% (7.4–42.0), and the 12‐month OS rate was 66.7% (42.5–82.5). Patients harboring EGFR ex20ins had similar ORR and PFS to those with other mutations. Six patients (28.6%) experienced grade 3 treatment‐related adverse events (TRAEs); hand‐foot syndrome was the most common grade 3 TRAE (2 patients; 9.5%). No grade ≥4 TRAEs were observed.ConclusionsThe combination of sintilimab and anlotinib demonstrated durable efficacy and was generally well tolerated in patients with NSCLC and uncommon EGFR mutations who had received prior standard‐of‐care treatments. (ClinicalTrials.gov identifier: NCT04790409).

Abstract As the most common intracranial malignancy in adults, glioblastoma (GBM) has limited improvement in prognosis with traditional treatment methods, such as surgery, chemotherapy, and radiotherapy. Currently, immunotherapy has revolutionized treatment outcomes for many cancers. However, special immunosuppressive microenvironment of GBM results in patients’ resistance to immunotherapy and poor prognosis. The mucosa-associated lymphoid tissue translocation gene 1 (MALT1) was reported to be involved in NF-κB activation and promote cancer cell’s proliferation and migration. And inhibition of MALT1 could attenuate the mesenchymal phenotype of GBM. Therefore, uncovering the role of MALT1 in the immunosuppressive microenvironment of GBM is of great importance. In this study, RNA-seq data of 169 GBM patients were downloaded from TCGA (The Cancer Genome Atlas) database and divided into MALT1_H (MALT1_High) and MALT1_L (MALT1_Low) groups based on MALT1’s expression level. First, the enrichment levels of the 29-immune signature were quantified in every GBM patient of MALT1_H and MALT1_L. Next, DEIGs (differentially expressed immune genes) were identified and used to establish an IPS (immune prognostic signature) by the LASSO (Least Absolute Shrinkage and Selection Operator) Cox regression analysis. PDYN was first found to be associated with GBM prognosis and was identified as a potential target of GBM. Based on three-gene IPS, we developed a predictive nomogram model to assess the prognosis of GBM patients. Additionally, MALT1 were proved to be a potential ideal therapeutic target for GBM. So, series of computer-aided technology were applied to screen favorable inhibitors of MALT1. In summary, we explored role of MALT1 in the suppressive immune microenvironment of GBM, established a novel MALT1-related nomogram model for prognostic prediction, and developed the targeted therapy for GBM in this study.

C-ros oncogene 1 (ROS1) fusion is a pathogenic driver gene in non-small cell lung cancer (NSCLC). Currently, clinical guidelines from the National Comprehensive Cancer Network (NCCN) have recommended molecular pathologic tests for patients with NSCLC, including the detection of the ROS1 gene. Crizotinib is a small molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and mesenchymal-epithelial transition (MET). In recent years, the efficacy of crizotinib in NSCLC patients with ROS1 fusion has been reported. Here, a 77-year-old woman was diagnosed with stage IVA lung adenocarcinoma harboring a novel low-density lipoprotein receptor (LDLR)-ROS1 fusion variant. This novel LDLR-ROS1 fusion was identified by targeted DNA next-generation sequencing (NGS) panel and then verified by RNA fusion panel based on amplicon sequencing. This patient benefited from subsequent crizotinib therapy and achieved progression-free survival of 15 months without significant toxic symptoms. Our case report recommended a promising targeted therapeutic option for patients with metastatic NSCLC with LDLR-ROS1 fusion and highlighted the importance of genetic testing for accurate treatment.

Purpose To develop a prediction model for estimating the expression of vascular endothelial growth factor receptor 2 (VEGFR2) in hepatocellular carcinoma (HCC) patients using clinical features and the contrast-enhanced MRI Liver Imaging Reporting and Data System (LI-RADS). Methods A total of 206 HCC patients were subjected to preoperative contrast-enhanced MRI, radical resection, and VEGFR2 immunohistochemistry labeling. The intensity of VEGFR2 expression was used to split patients into either the positive group or the negative group. For continuous data, the Mann-Whitney U test was employed, and for categorical variables, the χ2 test was utilized. Results VEGFR2-positivity was identified in 41.7% (86/206) of the patients. VEGFR2-positive HCCs were confirmed by higher serum alpha-fetoprotein (AFP) levels, larger tumor dimensions (either on MRI or upon final pathology), and a higher LI-RADS score (all p < 0.001). LI-RADS scores and AFP levels were independent predictors for high VEGFR2 expression. These two parameters were used to establish a VEGFR2-positive risk nomogram, which was validated to possess both good discrimination and calibration. The area under the curve was 0.830 (sensitivity 83.6%, specificity 72.5%) and the mean absolute error was 0.021. The threshold probabilities ranged between 0.07 and 0.95, and usage of the model contributed net benefits. Conclusion A nomogram including clinical features and contrast-enhanced MRI parameters was developed and was demonstrably effective at predicting VEGFR2 expression in HCC patients.

Importance Most older patients with esophageal cancer cannot complete the standard concurrent chemoradiotherapy (CCRT). An effective and tolerable chemoradiotherapy regimen for older patients is needed. Objective To evaluate the efficacy and toxic effects of CCRT with S-1 vs radiotherapy (RT) alone in older patients with esophageal cancer. Design, Setting, and Participants A randomized, open-label, phase 3 clinical trial was conducted at 23 Chinese centers between June 1, 2016, and August 31, 2018. The study enrolled 298 patients aged 70 to 85 years. Eligible participants had histologically confirmed esophageal cancer, stage IB to IVB disease based on the 6th edition of the American Joint Committee on Cancer (stage IVB: only metastasis to the supraclavicular/celiac lymph nodes) and an Eastern Cooperative Oncology Group performance status of 0 to 1. Data analysis was performed from August 1, 2020, to March 10, 2021. Interventions Patients were stratified according to age (<80 vs ≥80 years) and tumor length (<5 vs ≥5 cm) and randomly assigned (1:1) to receive either CCRT with S-1 or RT alone. Main Outcomes and Measures The primary end point was the 2-year overall survival rate using intention-to-treat analysis. Results Of the 298 patients enrolled, 180 (60.4%) were men. The median age was 77 (interquartile range, 74-79) years in the CCRT group and 77 (interquartile range, 74-80) years in the RT alone group. A total of 151 patients (50.7%) had stage III or IV disease. The CCRT group had a significantly higher complete response rate than the RT group (41.6% vs 26.8%; P = .007). Surviving patients had a median follow-up of 33.9 months (interquartile range: 28.5-38.2 months), and the CCRT group had a significantly higher 2-year overall survival rate (53.2% vs 35.8%; hazard ratio, 0.63; 95% CI, 0.47-0.85; P = .002). There were no significant differences in the incidence of grade 3 or higher toxic effects between the CCRT and RT groups except that grade 3 or higher leukopenia occurred in more patients in the CCRT group (9.5% vs 2.7%; P = .01). Treatment-related deaths were observed in 3 patients (2.0%) in the CCRT group and 4 patients (2.7%) in the RT group. Conclusions and Relevance In this phase 3 randomized clinical trial, CCRT with S-1 was tolerable and provided significant benefits over RT alone in older patients with esophageal cancer. Trial Registration ClinicalTrials.gov Identifier: NCT02813967.

BACKGROUND:Circular RNAs (CircRNAs) have been found to possess vital functions in tumorigenesis of various cancer types, including non-small cell lung cancer (NSCLC). The aim of this study was to identify and explore the diagnostic values of the newly found Toll interacting protein (TOLLIP)-derived circRNA (circTOLLIP) for liquid biopsy in NSCLC.METHODS:RNase R and actinomycin D assays were conducted to confirm the existence and stability of circTOLLIP. RT-qPCR was performed to identify the expression levels of circTOLLIP in NSCLC tumor tissues, whole blood, and cell lines. The diagnostic values were evaluated by receiver operating characteristic (ROC) curve analysis.RESULTS:CircTOLLIP was screened as a candidate biomarker and was found to be significantly down-regulated in both NSCLC tissues and cell lines. Interestingly, circulating circTOLLIP was also lower-expressed in the whole blood of patients with NSCLC compared to that of patients with benign lung disease and healthy controls. Importantly, the circulating circTOLLIP represented better diagnostic values in comparison to the traditional tumor markers (NSE, CYFR21-1, and CA72-4), and showed higher stability even though the whole blood was exposed to various tough conditions.CONCLUSIONS:Our findings indicate that circTOLLIP can be used as a non-invasive biomarker to distinguish early-stage NSCLC from benign lung diseases and from healthy controls, suggesting the potential application of circTOLLIP for liquid biopsy in NSCLC.